Familial aggregation of congenital cardiovascular malformations (CCVM) has been well established, but the underlying etiologic mechanisms are not understood. Preliminary studies from our collaborative efforts in a population-based investigation of CCVM in the Baltimore-Washington area suggest a concentration of familial aggregation and possibly monogenic inheritance of some left outflow tract defects; our additional clinical studies have identified possible forme fruste cardiac manifestations in some families. In the proposed project, comprehensive clinical evaluation of pedigrees and formal genetic analyses will identify possible sources of familial aggregation of variable cardiac phenotypes. Analyses will be performed on phenotypic data from nuclear family members obtained during clinical assessments and 2 dimensional and Doppler echocardiography, including M-mode measurements. To investigate the risks associated with left outflow tract defects, the families of children with hypoplastic left heart syndrome or coarctation of the aorta will be studied. For comparison of familial risk for occurrence and types of defects, relatives of children with d-transposition of the great arteries will be evaluated. Clinical assessment of control families obtain additional relatives of family members with documented heart defects. This protocol will maximize the efficiency of the formal genetic analysis using logistic regressive methods. This study will provide: (a) better understanding of etiologic relationships among abnormal cardiac phenotypes; (b) information concerning risk of occurrence of CCVM in relatives of probands with specific types of cardiac malformations; (c) elucidation of risk factors or covariates associated with these malformations; (d) genetic model fitting to determine the most parsimonious patterns of inheritance for these defects; (e) generation of hypotheses to be tested through molecular studies in humans and/or the development of animal models; and (f) identification of informative pedigrees for future genetic studies.